Blockade of angiogenic and non-angiogenic pathways is a promising strategy that has the potential to provide significant benefit to patients with advanced renal cell carcinoma (RCC). In order to individualize targeted therapies to the appropriate patients, it is necessary to identify and validate markers correlated with clinical benefit and/or toxicity. Preclinical studies have led us to a phase I/II trial of Bevacizumab and CCI- 779 to determine the safety and efficacy of the combination in patients with advanced RCC. We have observed very encouraging clinical antitumor activity from the first cohort of patients in the phase I portion of the study. Our long term goals are to identify and validate biomarkers predictive of clinical benefit as well as markers that can be used as surrogate endpoints of activity and toxicity in patients with advanced renal cell cancer treated with antiangiogenic therapies. Specific Aim 1: To identify tumor molecular markers associated with clinical benefit to the combination of CCI-779 and Bevacizumab in patients with metastatic renal cell cancer. Specific Aim 2: To evaluate circulating biomarkers associated with response and toxicity to the combination of CCI-779 and Bevacizumab in advanced renal cell cancer. Our proposal takes advantage of the current understanding of the molecular mechanisms of renal cell carcinoma and the availability of targeted agents that are active against this disease. Data generated in this study may help identify patients who will benefit from this treatment based on the molecular features of their tumors, a step forward in the development of individualized treatments for advanced renal cell carcinoma. Our proposed circulating biomarker studies will assess the effects of the treatment on different aspects of tumor neovascularization and may help identify patients at risk for toxicity from antiangiogenic treatments. This information will be extremely useful for the design of future trials using these agents in renal and other cancers and for future clinical practice. [unreadable] [unreadable] [unreadable]